Phenanthroindolizidines and phenanthroquinolizidines are a series of plant-derived natural alkaloids primarily found in the Asclepiadaceae and Moracea plant family. The leaves of these plants have been used to treat a number of diseases such as asthma, bronchitis, and rheumatism etc. since ancient times.1,2 Such interesting characteristics inevitably prompted scientists to identify the major therapeutic components in these plants, which led to the discovery of a series of bioactive natural products. To date, over sixty compounds have been isolated and characterized. R-tylophorine, R-antofine, and R-cryptopleurine (Scheme A) are well known representatives in the family that have been reported to have potent antitumor activity.3 Recently, an antitumor screening program launched by National Cancer Institute (NCI) has rekindled our interests in these compounds and greatly fascinated the progress of research in the discovery and development of more potent antitumor phenanthroindolizidines and phenanthroquinolizidines. However, the facts of low natural abundance and availability have prohibited researchers from discovering more exciting therapeutic candidates efficiently; therefore, total synthesis has been considered an effective approach to take place.

One major side effect prohibiting the use of natural alkaloids as therapeutic agents is their severe CNS toxicity, such as disorientation and ataxia.10 Analogs with higher polarity may be desirable to manipulate such side effects by preventing them from entering the blood brain barrier. Although a number of synthetic pathways to racemates or single isomers have been reported, to date, only a few polar antofine analogs with a C14-OH group have been synthesized and reported to have better antitumor activity in vivo compared with their natural counterparts; however, their activity in vitro was lower.11 More phenanthroindolizidines and phenanthroquinolizidines analogs with diverse structural features are urgently needed to extensively study the biological properties, especially antitumor activities. Previous methodologies to achieve these polar or non-polar active phenanthroindolizidine and phenanthroquinolizidine analogs all focused on modifications on rings -A, -C, and -D. There has been no synthetic method reported by far for making analogs with modifications on the ring-E, especially with practically versatile, efficient, and facile E-ring-derivatized advancements.